Type 2 diabetes mellitus results from an inadequate adaptation of the functional pancreatic β-cell mass in the face of insulin resistance. In turn, hyperglycemia per se has secondary adverse effects on β-cells. Indeed, several studies have shown that chronic elevation of blood glucose concentration impairs β-cell function, leading to the concept of “glucotoxicity” (1-7). Moreover, elevated glucose concentrations induce β-cell apoptosis in cultured islets from diabetes-prone Psammomys obesus (8), from human islets (9;10) and at higher concentrations in rodent islets (8;11;12). Various molecular mechanisms have been proposed to underlie glucose-induced β-cell dysfunction, including formation of advanced glycation end products (13), direct impairment of insulin gene transcription and proinsulin biosynthesis (14;15) and reduced binding activity of pancreatic duodenal homeobox 1 (PDX-1) (7). Recently, the present inventor and co-workers proposed a mechanism underlying glucose-induced β-cell apoptosis in human islets, which involves up-regulation of Fas receptors by elevated glucose levels (9). However, the mediator of glucose-induced Fas-expression and its role in glucotoxicity remains unknown.
Interleukin 1 receptor antagonist (IL-1Ra) is a mature glycoprotein of 152 amino acid (aa) residues. The protein has a native molecular weight of 25 kDa, and the molecule shows limited aa sequence homology to IL-1α (19%) and IL-1β (26%).
The effects produced by IL-1α and IL-1β result from the binding of these factors to two distinct cell surface receptors, IL-1R types I and II. Recent results suggest that only the type I receptor is capable of transducing a signal and producing a biological effect. The inhibitory action of IL-1Ra results from its binding to the type I IL-1R. Although this binding is of high-affinity (Kd=200 pM), it does not result in receptor activation (signal transduction), an effect attributed to the presence of only one receptor binding motif on IL-1Ra vs. two such motifs on IL-1α and IL-1β. Since the affinity of IL-1Ra for the type I receptor is comparable to that for IL-1α and IL-1β, down-regulation of IL-1 activity seems to be due to competitive inhibition. Notably, IL-1Ra also binds to the non-signal transducing type II IL-1R (Kd=7 nM), but with considerably lower affinity than that shown by IL-1β (Kd=0.3-2.0 nM). This makes sense teleologically in that two mechanisms designed to inhibit the actions of IL-1β (i.e., IL-1Ra binding to IL-1R type I and IL-1β binding to IL-1R type II) should not compete with each other.
It has been proposed to use IL-1β for mediating both impaired function and destruction of pancreatic β-cell during the development of autoimmune type 1 diabetes (16). In keeping with this, treatment of rodent islets with IL-1β results in a potent inhibition of insulin secretion followed by islet destruction (17-23). In human islets, IL-1β has further been shown to impair insulin release and to induce Fas expression enabling Fas-triggered apoptosis (9;24-28). Finally, activation of the nuclear transcription factor NF-κB is required for IL-1β-induced Fas expression (29-31). Part of these IL-1β effects are reminiscent of the toxic effects of elevated glucose concentrations.
Zaitsev et al. (60) propose the treatment of type 2 diabetes with imidazoline compounds.